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Summary: Background: We measured the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and re-infections in an adult community-based cohort in southern India. Methods: We conducted a 2-year follow-up on 1229 participants enrolled between May and October 2021. Participants provided vaccination histories, weekly saliva samples, and blood samples at 0, 6, 12, and 24 months. Salivary reverse transcription polymerase chain reaction (RT-PCR) and Meso-Scale Discovery panels were used for SARS-CoV-2 detection and anti-spike, anti-nucleocapsid immunoglobulin G quantification. Whole genome sequencing was performed on a subset of positive samples. SARS-CoV-2 infection incidence was measured across Pre-Omicron (May–December 2021), Omicron-I (December 2021–June 2022), and Omicron-II (July 2022–October 2023) periods. Findings: In total, 1166 (95%) participants with 83% seropositivity at baseline completed the follow-up, providing 2205 person-years of observation. Utilizing both RT-PCR and serology we identified 1306 infections and yielded an incidence rate of 591.3 per 1000 person-years (95% confidence interval, 559.6–624.3), which peaked during Omicron-I at 1418.1 per 1000 person-years (95% confidence interval, 1307.4–1535.6). During Omicron-I and II, neither prior infection nor vaccination conferred protection against infection. Overall, 74% of infections were asymptomatic. Interpretation: Integrated RT-PCR and serology revealed significant SARS-CoV-2 infection frequency, highlighting the prevalence of asymptomatic cases among previously infected or vaccinated individuals. This underscores the effectiveness of combining surveillance strategies when monitoring pandemic trends and confirms the role of non-invasive sampling in ensuring participant compliance, reflecting national transmission patterns. Funding: The study was funded by the Bill and Melinda Gates Foundation.